ES2814499T3 - Solid State Forms of Nilotinib Salts - Google Patents

Abstract

A crystalline form of Nilotinib fumarate designated as Form III, characterized by data selected from one or more of the following: a. an XRPD pattern having peaks at 5.5, 7.0, 11.0, 13.4, and 15.8 degrees two theta ± 0.2 degrees two theta; b. an XRPD pattern substantially as shown in Figure 1; c. and combinations of these data.

Description

DESCRIPTION

Solid State Forms of Nilotinib Salts

Cross reference to related requests

This application claims the benefit of US Provisional Application No. 62 / 307,841, filed March 14, 2016 and 62 / 418,745, filed November 17, 2016.

Technical field

The present invention relates to a crystalline form of Nilotinib fumarate called Form III, to preparation processes using the same, to pharmaceutical compositions comprising the same and said compound or compositions for use as a medicine.

Background

Nilotinib, 4-methyl-N- [3- (4-methyl-1H-imidazol-1-yl) -5- (trifluoromethyl) phenyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] -benzamide, which has the following formula:

is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML) and, in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive CML in adult patients whose disease has progressed or who they cannot tolerate other therapies that include Imatinib. Nilotinib is administered as a hydrochloride salt in the form of capsules that are marketed in the US and EU under the name Tasigna®.

PCT publications WO 2007/015870 ("WO'870"), WO 2007/015871, WO2011 / 0163222 ("WO'222") and WO 2010/054056 ("WO'056") describe the Nilotinib base and various salts of Nilotinib, and crystalline and amorphous forms thereof. Crystalline forms exist in solvate, anhydrous or hydrated forms. WO'222 describes crystal forms I and II of Nilotinib fumarate as well as various crystal forms of Nilotinib tartrate.

Polymorphism, the appearance of different crystal forms, is a property of some molecules and molecular complexes. A single compound, such as Nilotinib or a salt thereof, can give rise to a variety of polymorphs that have different crystal structures and physical properties such as melting point, thermal behaviors (for example, measured by thermogravimetric analysis - "TGA", or Differential Scanning Calorimetry - "DSC"), X-ray powder diffraction pattern (XRPD), infrared absorption fingerprint, Raman absorption fingerprint and solid state (13C-) NMR spectrum. One or more of these techniques can be used to distinguish different polymorphic forms of a compound.

Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient can possess different properties. Such variations in the properties of different salts and solid state forms and solvates can provide a basis for improving the formulation, for example, facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as stability). chemistry) and shelf life. These variations in the properties of different salts and solid state forms can also provide improvements to the final dosage form, for example if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient can also give rise to a variety of polymorphs or crystalline forms, which in turn can provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient. to provide an improved product.

Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials that have desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystalline forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide the opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). Extends the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, for example a different crystal habit, higher crystallinity or polymorphic stability that can offer better processing characteristics or handling, improved dissolution profile or improved pot life. For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Nilotinib and its salts, for example Nilotinib fumarate. Summary

The scope of the invention is defined exclusively by the appended claims. The present disclosure further relates to other subject matter which, provided it exceeds the scope of the claims, does not form part of the invention but only for reference.

The present description refers to solid state forms of Nilotinib fumarate cocrystals and Nilotinib L-tartaric acid hydrochloride, to the processes for their preparation and to the pharmaceutical compositions comprising these solid state forms.

The present disclosure also relates to uses of the solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure, to prepare Nilotinib, Nilotinib salts, such as Nilotinib HCl and its solid state forms, and other solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals.

In another aspect, the present disclosure encompasses solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals for use in the preparation of pharmaceutical compositions and / or formulations for use in medicine, preferably for the cancer treatment, in particular for the treatment of chronic myelogenous leukemia (CML).

The present disclosure also encompasses the uses of solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals for the preparation of pharmaceutical compositions and / or formulations. The present disclosure further provides pharmaceutical compositions comprising any one or a mixture of the solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals in accordance with the present disclosure.

In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising the solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride co-crystals, or of pharmaceutical compositions comprising the solid state forms of Nilotinib fumarate. and / or cocrystals of Nilotinib L-tartaric acid hydrochloride and at least one pharmaceutically acceptable excipient.

The present disclosure further encompasses processes for preparing said Nilotinib fumarate pharmaceutical formulations and / or Nilotinib L-tartaric acid hydrochloride cocrystals which comprise combining the Nilotinib fumarate state forms and / or Nilotinib L-tartaric acid hydrochloride cocrystals. , or pharmaceutical compositions comprising them and at least one pharmaceutically acceptable excipient.

Solid state forms as defined herein as well as pharmaceutical compositions or formulations of the solid state form of Nilotinib fumarate and / or cocrystalline forms of Nilotinib L-tartaric acid hydrochloride can be used as medicaments, particularly for the treatment of cancer, especially CML, comprising administering a therapeutically effective amount of the solid state form of Nilotinib fumarate and / or cocrystalline forms of Nilotinib L-tartaric acid hydrochloride of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject suffering from cancer or otherwise in need of treatment.

The present disclosure also provides the solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above, for use in medicine, preferably to treat cancer, in particular to treat CML.

The present disclosure also provides uses of the solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure, or at least one of the above pharmaceutical compositions or formulations for the manufacture of medicaments for treat cancer, in particular for the treatment of CML.

Brief description of the drawings

Figure 1 shows an X-ray powder diffraction (XRPD) pattern of Nilotinib fumarate Form III. Figure 2 shows an XRPD pattern of Form I Nilotinib L-tartaric acid hydrochloride cocrystals. Figure 3 shows an XRPD pattern of Form II Nilotinib L-tartaric acid hydrochloride cocrystals. Figure 4 shows a solid state 13C-NMR spectrum of Nilotinib fumarate Form III.

Figure 5 shows a Fourier transform infrared (FTIR) spectrum of Nilotinib fumarate Form III.

Figure 6 shows a Raman spectrum of Nilotinib fumarate Form III.

Figure 7 shows a DSC thermogram of Nilotinib fumarate Form III.

Figure 8 shows a TGA thermogram of Nilotinib fumarate Form III.

Figure 9 shows an FTIR spectrum of Form I Nilotinib L-tartaric acid hydrochloride cocrystals. Figure 10 shows a Raman spectrum of Form I Nilotinib L-tartaric acid hydrochloride cocrystals. Figure 11 shows a solid state 13C NMR spectrum of Form I co-crystals of Nilotinib L-tartaric acid hydrochloride.

Detailed Description of Illustrative Embodiments

The scope of the invention is defined exclusively by the appended claims. The present disclosure further relates to other subject matter which, provided it exceeds the scope of the claims, does not form part of the invention but only for reference.

The present disclosure relates to a solid state form of Nilotinib fumarate and to solid state forms of cocrystals of Nilotinib L-tartaric acid hydrochloride, to processes for their preparation and to pharmaceutical compositions comprising any of these forms in solid state and / or combinations thereof. The disclosure also relates to the conversion of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure into other solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals. , Nilotinib, other Nilotinib salts, such as Nilotinib HCl and solid state forms thereof.

Solid state forms according to the present disclosure may have advantageous properties selected from at least one of: chemical or polymorphic purity, fluidity, solubility, dissolution rate, bioavailability, crystal morphology or habit, stability, such as chemical stability, as well such as thermal and mechanical stability with respect to polymorphic conversion, dehydration stability and / or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies, and advantageous processing and handling characteristics such as compressibility and density apparent. Reference may be made in this document to a crystalline form characterized by graphical data "as depicted in" a figure. Such data include, for example, X-ray powder diffractograms and solid state NMR spectra. As is well known in the art, graphical data potentially provides additional technical information to further define the respective solid state shape (a so-called "fingerprint") that cannot necessarily be described by reference to numerical values or peak positions only. In any case, the skilled person will understand that said graphical representation of data may be subject to small variations, for example, in maximum relative intensities and peak positions due to factors such as variations in the response of the instrument and variations in the concentration and purity of the shows, which are well known to experts. However, the skilled person could easily compare the graphical data in the figures in this document with the graphical data generated for an unknown crystal shape, and confirm whether the two graphical data sets characterize the same crystal shape or two crystal shapes. different. A crystalline form of Nilotinib or a Nilotinib salt, for example, of Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals referred to herein as characterized by graphical data "as shown in" a figure, therefore, will be understood to include any crystalline form of Nilotinib fumarate, characterized with the graphical data with such small variations, that they are well known to the skilled person, compared to the figure.

A solid state (or polymorphic) form may be referred to herein as polymorphically pure or substantially free from any other solid state (or polymorphic) form. As used in this document In this context, the term "substantially otherwise free" will be understood to mean that the solid state form contains about 20% (w / w) or less, about 10% (w / w) or less, about 5% (w / w) or less, about 2% (w / w) or less, about 1% (w / w) or less, or about 0% (w / w) of any other form of the subject compound as measured, for example, by XRPD. Therefore, it will be understood that the solid state forms of Nilotinib fumarate described herein as substantially free from any other solid state form contain more than about 80% (w / w), more than about 90% (w / w), more than about 95% (w / w), more than about 98% (w / w), more than about 99% (w / w), or about 100% of the form in solid state subject to Nilotinib fumarate or Nilotinib hydrochloride L-tartaric acid cocrystals. Accordingly, in some embodiments of the disclosure, the disclosed solid state forms of Nilotinib fumarate or Nilotinib L-tartaric acid co-crystals may contain from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), or from about 5% to about 10% (w / w) of one or more solid state forms of the same Nilotinib fumarate or acid Nilotinib hydrochloride cocrystals L-tartaric.

As used herein, unless otherwise noted, the XRPD peaks reported herein are measured using CuKa radiation, A = 1.54184 A. Preferably, the XRPD peaks reported herein document are measured using CuKa radiation, A = 1.54184 A, at a temperature of 25 ± 3 ° C. Alternatively, if an instrument with a different wavelength is used, for example when using the high resolution XRD method such as synchrotron, the data can be corrected to a wavelength of 1.54184 respectively.

As used herein, the term "isolated" in reference to the solid state forms of Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure corresponds to the solid state form of fumarate of Nilotinib or Nilotinib L-tartaric acid hydrochloride cocrystals that is physically separated from the reaction mixture in which it is formed.

One thing, eg, a reaction mixture, may be characterized herein as being or allowed to reach "room temperature", often abbreviated "RT". This means that the temperature of the thing is close to, or equal to, that of the space, for example, the room or fume hood, in which the thing is located. Typically, the ambient temperature is about 20 ° C to about 30 ° C, or about 22 ° C to about 27 ° C, or about 25 ° C.

In this document, a process or step may be referred to as taking place "overnight". This refers to a time interval, for example, for the process or step, spanning the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or from about 10 to about 18 hours, typically about 16 hours.

As used herein, the term "wet crystalline form" refers to a polymorph that was not dried using any conventional technique to remove residual solvent. Examples of such conventional techniques can be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, and the like.

As used herein, the term "dry crystalline form" refers to a polymorph that was dried using any conventional technique to remove residual solvent. Examples of such conventional techniques may be, but are not limited to, evaporation, vacuum drying, oven drying, drying under nitrogen flow, and the like.

As used herein, and unless otherwise indicated, the term "anhydrous" in relation to Nilotinib fumarate crystalline cocrystals or Nilotinib hydrochloride L-tartaric acid refers to Nilotinib fumarate crystalline cocrystals. or Nilotinib L-tartaric acid hydrochloride, which does not include crystalline water (or other solvents) in a defined stoichiometric amount within the crystal. Furthermore, an "anhydrous" form does not contain more than about 1% (w / w) of water or organic solvents as measured, for example, by TGA.

The term "solvate", as used herein and unless otherwise indicated, refers to a crystalline form that incorporates a solvent into the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate can be present in a stoichiometric or non-stoichiometric amount.

The amount of solvent employed in a chemical process, for example a reaction or a crystallization may be referred to herein as various "volumes" or "vol" or "V". For example, a material can be called suspended in 10 volumes (or 10 vol or 10 V) of a solvent. In this context, this expression would be understood to mean milliliters of solvent per gram of suspended material, so suspending 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material being suspended or, in this example, 50 ml of solvent. On In another context, the term "v / v" can be used to indicate the number of volumes of a solvent that is added to a liquid mixture based on the volume of that mixture. For example, the addition of MTBE (1.5 v / v) to a 100 ml reaction mixture would indicate that 150 ml of MTBE was added.

As used herein, the term non-hygroscopic in relation to the crystalline forms of the present disclosure refers to less than about 1.0% (w / w) absorption of water at about 25 ° C and about 80% relative humidity (RH), by the crystalline forms of the present disclosure determined, for example, by TGA. The water can be, for example, atmospheric water.

As used herein, the term "reduced pressure" refers to a pressure from about 10 mbar to about 50 mbar.

As used herein, and unless otherwise indicated, the term "thermodynamic stability" in relation to the solid state forms of the present disclosure refers to the resistance of the solid state form to polymorphic conversion. under certain conditions, for example heating, melting or dissolving. In some embodiments, the term refers to less than about 20% (w / w), about 10% (w / w), about 5% (w / w), about 1% (w / w) , about 0.5% (w / w), or about 0% (w / w) conversion of the solid state forms of the present disclosure to any other solid state form of Nilotinib fumarate or hydrochloride cocrystals of Nilotinib L-tartaric acid, measured by XRPD. In some embodiments, the conversion is from about 1% (w / w) to about 20% (w / w), about 1% (w / w) to about 10% (w / w), or about 1% (w / w) to about 5% (w / w).

As used herein, the T17 form of Nilotinib HCl refers to the crystalline form provided in WO'056, which can be characterized by a powder X-ray diffraction pattern having peaks at 5.7, 9.8, 15.0, 15.8 and 17.3 degrees two theta ± 0.2 degrees two theta. Nilotinib HCl Form T17 can be further characterized by a powder X-ray diffraction pattern having additional peaks at approximately 7.5, 11.4, 18.6, 19.6 and 20.7 degrees two theta ± 0 , 2 degrees two theta or approximately 7.6, 11.4, 18.7, 19.7 and 20.7 degrees two theta ± 0.2 degrees two theta.

The present disclosure comprises a crystalline form of Nilotinib fumarate designated Form III. Nilotinib fumarate crystalline form III can be characterized by data selected from one or more of the following: an XRPD pattern that has peaks at 5.5, 7.0, 11.0, 13.4, and 15.8 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as shown in Figure 1; a solid state 13C NMR spectrum having characteristic peaks at 168.9, 159.1, 135.4 and 114.7 ± 0.2 ppm; a solid state 13C NMR spectrum substantially as shown in Figure 4; a solid state 13C NMR spectrum having the following absolute chemical shift differences from a peak at 119.0 ppm ± 1 ppm to 49.9, 40.1, 16.4 and -4.3 ppm ± 0.1 ppm; a solid state 13C NMR spectrum having a chemical shift difference from a peak at 119.0 ppm ± 1 ppm to 40.1 ppm ± 0.1 ppm; and combinations of these data.

Nilotinib fumarate crystalline form III can be further characterized by data selected from one or more of the following: an XRPD pattern that has peaks at 5.5, 7.0, 11.0, 13.4, and 15.8 degrees two theta ± 0.2 degrees two theta, and which also has one, two, three, four, five, six or seven additional peaks selected from 14.0, 14.9, 16.3, 20.4, 20.5 , 20.9 and 25.3 degrees two theta ± 0.2 degrees two theta; an FTIR spectrum having peaks at 3348, 1676, 1560, 1404 and 1296 ± 4 cm -1; an FTIR spectrum substantially as shown in Figure 5; a Raman spectrum having peaks at 1668, 1614, 1407 and 1306 ± 4 c rr1; a Raman spectrum substantially as shown in Figure 6; melting DSC endothermic peak at about 228 ° C (start); a DSC thermogram substantially as shown in Figure 7; a TGA thermogram substantially as shown in Figure 8; and combinations of these data.

The crystalline form III of Nilotinib fumarate can be further characterized by an XRPD pattern comprising the following peaks ± 0.2 degrees two theta):

continuation

The crystalline form III of Nilotinib fumarate can be further characterized by a 13 C NMR spectrum in the state solid having the following peaks at: 10.9, 19.3, 107.1, 108.5, 110.7, 111.6, 114.7, 119.0, 123.0, 125.2, 128, 2, 128.8, 130.1, 132.9, 134.7, 135.4, 136.2, 137.4, 141.2, 145.1, 147.7, 159.1, 163.9, 168.0, 168.9 ppm ± 0.2 ppm).

The crystalline form III of Nilotinib fumarate can be further characterized by an FTIR spectrum comprising the following peaks: 3348, 3151, 3056, 3071, 2924, 2463, 1698, 1676, 1621, 1588, 1560, 1527, 1489, 1446, 1404 , 1320, 1296, 1231, 1188, 1167, 1119, 1085, 1040, 993, 922, 877, 846, 822, 800, 760, 746, 737, 708, 688, 649, 626, 609, 585 and 543 cm- 1 ± 1 cm-1.

The crystalline form III of Nilotinib fumarate can be further characterized by a Raman spectrum comprising the following peaks: 3073, 2925, 1668, 1614, 1600, 1570, 1487, 1443, 1407, 1382, 1306, 1278, 1234, 1118, 1086 , 1040, 1028, 999, 992, 973, 903, 795, 759, 709, 685, 636 and 610 cm-1 ± 4 cm-1.

Nilotinib fumarate form III can be an anhydrous form.

The crystalline Form III of Nilotinib fumarate can be characterized by each of the above characteristics alone and / or by all possible combinations. For example, the crystalline form III of Nilotinib fumarate can be characterized by a PXRD pattern as shown in Figure 1 and also by an FTIR spectrum that has peaks at 3348, 1676, 1560, 1404, and 1296 ± 4 cm-1.

Nilotinib fumarate form III may have advantageous properties selected from at least one of: chemical or polymorphic purity, flowability, solubility, wettability, dissolution rate, bioavailability, crystal morphology or habit, stability, such as chemical stability, as well as thermal and mechanical stability with respect to polymorphic conversion, dehydration stability and / or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies, and advantageous processing and handling characteristics such as compressibility or bulk density. In particular, the crystalline form III of the Nilotinib fumarate of the present disclosure is chemically and polymorphically stable, as confirmed, for example, under conditions of long-term stability at 5 ° C and conditions of accelerated stability at 25 ° C / 60. % RH with desiccant. Furthermore, compared to the Nilotinib fumarate forms I and II described in WO'222, the Nilotinib fumarate form III of the present disclosure has higher crystallinity and is thermodynamically more stable. A stable polymorph (which does not convert to other forms or a mixture of forms), facilitates API handling and formulation, and therefore enables reliable and reproducible formulation manufacturing processing. As a result, the formulation process allows easily reproducible formulations in terms of solubility, bioavailability, etc. Furthermore, Form III can be obtained from various pharmaceutically acceptable solvents, while Forms I and II are obtained from 2,2,2-trifluoroethanol (TFE), which is a toxic solvent. Being able to produce Nilotinib fumarate Form III from a less toxic solvent system offers a clear advantage over Forms I and II of WO'222. Furthermore, for solvated forms of a crystalline compound (such as Forms I and II of WO'222) there is always the possibility that some of the solvent will be lost during the drying and processing steps, which is generally disadvantageous in view of potential problems with the defined weight of the material. In contrast, the Nilotinib fumarate form III of the present disclosure is an anhydrous form and therefore has no risk of solvent loss during the production and / or drying steps.

In another embodiment, the present disclosure comprises a Nilotinib L-tartaric acid hydrochloride cocrystal designated as Form I. Nilotinib L-tartaric acid hydrochloride cocrystals Form I can be characterized by data selected from one or more of the following: a XRPD pattern having peaks at 5.9, 8.1, 14.2, 14.6, and 19.7 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as shown in Figure 2; a solid state 13C NMR spectrum having characteristic peaks at 174.5, 168.4, 157.3 and 130.8 ± 0.2 ppm; a solid state 13C NMR spectrum substantially as shown in Figure 11; a solid state 13C NMR spectrum having the following absolute chemical shift differences from a peak at 117.2 ppm ± 1 ppm to 57.3, 51.2, 40.1 and 13.6 ppm ± 0.1 ppm , respectively; a solid state 13C NMR spectrum having a chemical shift difference from a peak at 117.2 ppm ± 1 ppm to 40.1 ppm ± 0.1 ppm; and combinations of these data.

Nilotinib L-tartaric acid hydrochloride form I cocrystals can be further characterized by data selected from one or more of the following: an XRPD pattern having peaks at 5.9, 8.1, 14.2, 14, 6 and 19.7 degrees two theta ± 0.2 degrees two theta; and also has one, two, three, four or five additional peaks selected from 11.1, 11.8, 17.1, 18.6 and 26.2 degrees two theta ± 0.2 degrees two theta; an FTIR spectrum having peaks at 3369, 1732, 1653, 1531, and 1447 ± 4; an FTIR spectrum substantially as shown in Figure 9; a Raman spectrum having peaks at 1649, 1613, 1447 and 1306 ± 4 cm -1; a Raman spectrum substantially as shown in Figure 10; and combinations of these data.

The crystalline form I of Nilotinib L-tartaric acid hydrochloride can be further characterized by an XRPD pattern comprising the following peaks ± 0.2 degrees two theta):

continuation

The crystalline form I of Nilotinib L-tartaric acid hydrochloride can be further characterized by a solid state 13C NMR spectrum having the following peaks at: 10.3, 17.1, 107.1, 109.7, 113.1 , 117.2, 119.1, 120.6, 122.0, 125.0, 130.8, 132.8, 135.7, 138.0, 144.5, 148.6, 157.3, 168 , 4 and 174.5 ppm ± 0.2 ppm.

The crystalline form I of Nilotinib L-tartaric acid hydrochloride can be further characterized by an FTIR spectrum comprising the following peaks: 3369, 3231, 3104, 2933, 2556, 1732, 1653, 1614, 1590, 1568, 1531, 1483, 1447 , 1417, 1377, 1351, 1305, 1258, 1226, 1208, 1175, 1132, 1095, 1047, 875, 809, 786, 698, 686 and 655 cm-1 ± 1 cm-1. The crystalline form I of Nilotinib L-tartaric acid hydrochloride can be further characterized by a Raman spectrum comprising the following peaks: 3071, 2935, 1735, 1649, 1613, 1586, 1561, 1447, 1418, 1396, 1377, 1335, 1306 , 1259, 1210, 1113, 1046, 1031, 1020, 997, 970, 933, 850, 803, 761, 704, 682, 638 and 613 cm-1 ± 4 cm-1.

The ratio of Nilotinib hydrochloride to L-tartaric acid in cocrystals Form I is approximately 2: 1, as determined by NMR (see Example 4).

The crystalline form I of Nilotinib L-tartaric acid hydrochloride can be a solvate such as ethanolate or methanolate or a hydrate. Preferably, crystalline form I of Nilotinib L-tartaric acid hydrochloride is a hydrate.

Nilotinib L-tartaric acid hydrochloride Form I can be characterized by each of the above characteristics alone and / or by all possible combinations. For example, crystalline form I of Nilotinib L-tartaric acid hydrochloride can be characterized by a PXRD pattern as shown in Figure 2 and also by an FTIR spectrum that has peaks at 3369, 1732, 1653, 1531 and 1447 ± 4 cm-1.

Nilotinib L-tartaric acid hydrochloride Form I can be characterized by each of the above characteristics alone and / or by all possible combinations. For example, crystalline form I of Nilotinib L-tartaric acid hydrochloride can be characterized by a PXRD pattern as shown in Figure 2 and also by an FTIR spectrum that has peaks at 3369, 1732, 1653, 1531 and 1447 ± 4 cirr1.

Nilotinib L-tartaric acid hydrochloride Form I can have advantageous properties selected from at least one of: chemical or polymorphic purity, fluidity, solubility, wettability, dissolution rate, bioavailability, crystalline morphology or habit, stability, such as chemical stability, as well as thermal and mechanical stability with respect to polymorphic conversion, dehydration stability and / or storage stability, a lower degree of hygroscopicity, low content of residual solvents, tendencies adhesives and advantageous processing and handling characteristics such as compressibility or bulk density. In particular, the crystalline form I of the Nilotinib L-tartaric acid hydrochloride of the present disclosure has a high bulk density, as measured by the European Pharmacopoeia 2.9.34 / USP method <616> (GMP000582 / 5), compared, by For example, with Nilotinib HCl form B described in WO'870. A material that has a higher bulk density typically exhibits better filterability and flowability.

Nilotinib L-Tartaric Acid Hydrochloride Form I may have advantageous properties selected from at least one of: chemical or polymorphic purity, fluidity, solubility, wettability, dissolution rate, bioavailability, crystal morphology or habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, dehydration stability and / or storage stability, a lower degree of hygroscopicity, low content of residual solvents, adhesive tendencies and advantageous processing and handling characteristics such as compressibility. or apparent density. In particular, the crystalline form I of the Nilotinib L-tartaric acid hydrochloride of the present disclosure has a high bulk density, as measured by the European Pharmacopoeia 2.9.34 / USP method <616> (GMP000582 / 5), compared, by For example, with Nilotinib HCl form B described in WO'870. A material that has a higher bulk density typically exhibits better filterability and flowability.

Good filterability is a prerequisite to enable API production on an industrial scale. Good flowability of a powder is particularly important in high volume formulation of API in solid dosage forms, which requires fast, uniform and consistent filling of cavities such as capsules or tablet presses. Poor flow characteristics cause slow and uneven press feed and difficulties in ensuring consistent and reproducible filling of cavities.

Therefore, Nilotinib L-tartaric acid hydrochloride Form I of the present disclosure has favorable technological (physical and mechanical) properties, offering advantages during handling and processing, for example, in tablet formulation processes.

In yet another embodiment, the present disclosure comprises a Nilotinib L-tartaric acid hydrochloride cocrystal designated Form II. Nilotinib L-tartaric acid hydrochloride form II cocrystals may be characterized by data selected from one or more of the following: an XRPD pattern having peaks at 4.2, 7.2, 8.4, 11.7 and 12.6 degrees two theta ± 0.2 degrees two theta; an XRPD pattern substantially as shown in Figure 3; or combinations of these data.

Nilotinib L-tartaric acid hydrochloride form II cocrystals can be further characterized by an XRPD pattern that has peaks at 4.2, 7.2, 8.4, 11.7 and 12.6 degrees two theta ± 0, 2 degrees two theta; and it also has one, two, three, four, or five additional peaks selected from 14.3, 17.6, 23.4, 24.6, and 25.4 degrees two theta ± 0.2 degrees two theta.

The present disclosure also provides the use of solid state forms of Nilotinib fumarate and / or Nilotinib L-tartaric acid hydrochloride cocrystals to prepare other solid state forms of Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals. , Nilotinib, other Nilotinib salts, such as Nilotinib HCl and solid state forms thereof.

The present disclosure further encompasses processes for preparing Nilotinib or solid state forms thereof. The process for preparing Nilotinib or solid state forms thereof comprises preparing the solid state form of Nilotinib fumarate or any of the Nilotinib L-tartaric acid hydrochloride cocrystals, according to the present disclosure, and converting it to Nilotinib or forms. in solid state of the same. The conversion can be done, for example, by reacting the solid state form of Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals described herein with a suitable base to obtain Nilotinib.

The present disclosure further encompasses processes for preparing other Nilotinib salts, such as Nilotinib HCl, or solid state forms thereof. The process comprises preparing the solid state form of Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals of the present disclosure and converting them to another Nilotinib salt. The conversion can be done, for example, by a process comprising converting Nilotinib fumarate or Nilotinib L-tartaric acid hydrochloride cocrystals into Nilotinib according to the above procedure and reacting the obtained Nilotinib with an appropriate acid to obtain the salt. corresponding acid addition. Alternatively, the Nilotinib salt can be prepared by changing the salt, i.e., reacting Nilotinib fumarate, Nilotinib hydrochloride cocrystals, L-tartaric acid, or any of its solid state forms, with an acid, which has a pKa that is less than the pKa of fumaric acid or hydrochloric acid, respectively.

In another embodiment, the present disclosure encompasses the use of the above-described Nilotinib fumarate solid state form or Nilotinib L-tartaric acid hydrochloride cocrystal forms for the preparation of pharmaceutical compositions and / or formulations.

The present disclosure further provides pharmaceutical compositions comprising the solid state form of Nilotinib fumarate or cocrystal forms of Nilotinib L-tartaric acid hydrochloride according to the present disclosure.

In yet another embodiment, the present disclosure encompasses pharmaceutical formulations comprising the above-described solid state form of Nilotinib fumarate or cocrystalline forms of Nilotinib L-tartaric acid hydrochloride and / or combinations thereof, or a pharmaceutical composition as described. described above, and at least one pharmaceutically acceptable excipient.

The present disclosure further encompasses processes for preparing such formulations which comprise combining the above-described Nilotinib fumarate solid state form or Nilotinib L-tartaric acid hydrochloride cocrystalline forms and / or combinations thereof and at least one pharmaceutically acceptable excipient. . In another embodiment, the present disclosure encompasses the above-described solid state form of Nilotinib fumarate or co-crystal forms of Nilotinib L-tartaric acid hydrochloride for use in medicine, preferably for the treatment of cancer, for example, the treatment of the CML.

The present disclosure also provides the use of the solid state form of Nilotinib fumarate or co-crystal forms of Nilotinib L-tartaric acid hydrochloride of the present disclosure, or at least one of the pharmaceutical compositions or formulations described above for the manufacture of a medicine to treat cancer, particularly to treat CML.

Having described the disclosure with reference to certain preferred embodiments, other embodiments will be apparent to one of ordinary skill in the art from a consideration of the specification. The disclosure is further illustrated with reference to the following examples which describe in detail the preparation of the composition and the methods of use of the disclosure. It will be apparent to those skilled in the art that many modifications can be made, both to materials and to methods, without departing from the scope of the disclosure. The scope of the invention is defined exclusively by the appended claims. The present disclosure further relates to other subject matter which, provided it exceeds the scope of the claims, does not form part of the invention but only for reference.

Analytical methods

X-ray powder diffraction pattern method ("XRPD"):

The sample, after being sprayed into a mortar, is applied directly to a silicone plate support. The powder X-ray diffraction pattern was measured with a Philips X'Pert PRO powder X-ray diffractometer, equipped with an irradiation source of Cu = 1.54184 A (Angstrom) and an X'Celerator detector (2.022 ° twenty). Scan parameters: angle range: 3-40 °, step size 0.0167, time per step 37s, continuous scan. The peak positions described were determined using silicon powder as an internal standard in a mixture with the measured sample.

1H-NMR method:

The NMR spectrum was recorded on a Bruker Avance DRX 500 spectrometer using standard Bruker pulse sequences, at 25 ° C in DMSO-cfe as solvent and TMS as internal standard.

Differential Scanning Calorimetry ("DSC")

DSC analysis was performed on Q1000 MDSC (TA instruments) with a heating rate of 10 ° C / min, under a nitrogen flow of 50 ml / min. A sealed aluminum container with orifice was used and the mass of the sample was approximately 1-5 mg.

Thermogravimetric Analysis (TGA)

TGA analysis was performed on the Mettler Toledo TG-DSC 1 and Mettler Toledo TGA / SDTA 851e instruments with a heating rate of 10 ° C / min and under a nitrogen flow of 30 ml / min. A standard aluminum open tray was used, the mass of the sample was 1 to 10 mg.

Fourier transform infrared spectroscopy ("FTIR")

The sample (1-2 mg) was triturated with 200-300 mg of dry potassium bromide and the mixture was compressed into a granule with a pressure of 700 MPa. The spectrum of the sample was recorded in the range of 4000 to 400 cirr1, with resolution of 2 cirr1 and 16 scans. For the background spectrum, air (vacuum sample compartment) was used. Analysis was performed on Nicolet 6700.

FT-Raman ("Raman") spectroscopy

Raman spectra were acquired on a Nicolet 6700 interferometer equipped with an NXR FT-Raman module. Nd-YAG laser (1064 nm, 500 mW) was used to excite the sample. The spectrometer uses a CaF ² beam splitter and a liquid nitrogen cooled Ge detector. Spectra were recorded at a resolution of 4 cirr1.

Solid State Nuclear Magnetic Resonance ("ssNMR")

Solid state 13C NMR spectra were recorded with variable amplitude cross polarization, magic angle rotation, and high power proton decoupling using a BRUKER Avance II spectrometer operating at 125 MHz and room temperature (approximately 25 ° C, uncontrolled). . A probe using zirconia rotors with an outer diameter of 4 mm was used. The operating conditions were: Contact time: 2 ms; recycle delay: 2 s 1024 scans; 11 kHz rotational speed. Chemical shifts were referenced by a glycine substitution sample (carboxyl carbon chemical shift assigned 176.03 ppm relative to tetramethylsilane signal).

Examples

Nilotinib base can be prepared according to the process described in WO'222.

Nilotinib hydrochloride can be prepared according to the process described in WO'056.

Example 1: Preparation of Nilotinib Fumarate Form III

Nilotinib base (1.0 g, 1.84 mmol) was suspended in ethanol, 96% (50 ml) and acetic acid (1 ml). Fumaric acid (0.25 g, 2.13 mmol) was added. The reaction mixture was heated to about 80 ° C and the obtained solution was filtered. The filtrate was cooled to 20-25 ° C. The precipitate was filtered, washed with ethanol, abs. to obtain 0.57 g (48.0%) of Nilotinib fumarate Form III, as confirmed by XRPD.

Example 2. Preparation of Nilotinib Fumarate Form III

Nilotinib base (1.0 g, 1.84 mmol) was suspended in 1-butanol (32 ml) and methanol (8 ml). Fumaric acid (0.25 g, 2.13 mmol) was added. The reaction mixture was heated to about 85 ° C and the obtained solution was filtered. The filtrate was cooled to 0-5 ° C and stirred for approximately 2 h. The precipitate was filtered, washed with 1-butanol / methanol 4: 1 (5 ml) and dried in a vacuum oven at 70 ° C / 20 mbar / 10 h to obtain 1.02 g (85.8%) of Nilotinib fumarate Form III, as confirmed by XRPD.

Example 3. Preparation of Nilotinib Fumarate Form III

Nilotinib base (10.0 g, 18.4 mmol) was suspended in 1-butanol (400 ml) and ethanol, abs. (100 ml). Fumaric acid (2.5 g, 21.3 mmol) was added to the suspension. The reaction mixture was heated to 90-95 ° C and the obtained solution was filtered. The filtrate was cooled to 45 ° C and stirred for approximately 2 h, then cooled to 20 ° C and stirred for approximately 18 h. The precipitate was filtered, washed with 1-butanol / ethanol, abs. = 1: 4 (50 ml) and ethanol, abs. (10 ml). The solid obtained was dried in a vacuum oven at 70 ° C / 20 mbar / 10 h to obtain 11.13 g (93.6%) of Form III Nilotinib fumarate, as characterized by XRPD (Figure 1) .

Example 4. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) A suspension of Nilotinib hydrochloride (1.0 g) and L-tartaric acid (0.5 g) was dissolved in methanol : isopropanol 1: 1 (20 ml) at 70-75 ° C. The obtained solution was cooled to room temperature (RT) and stirred for about 3 days. The precipitate obtained was filtered and washed with 1: 1 methanol: isopropanol. The solid was heated (50 mg) to 130 ° C (10 ° C / min) under a nitrogen flow (10 ml / min) to provide Form I Nilotinib hydrochloride L-tartaric acid cocrystals, as characterized by XRPD (Figure 1).

Example 5. Preparation of Nilotinib L-tartaric acid hydrochloride cocrystals Form I (for reference only) A suspension of Nilotinib base (5.0 g) in abs. Ethanol. (150 ml) was heated under reflux. An ethanolic hydrochloric acid solution (1.25 M, 9 ml) was added dropwise to the suspension to provide a solution. The obtained solution was filtered and the filtrate was heated to 70-75 ° C. A solution of L-tartaric acid (1.55 g) in abs ethanol was added. (15 ml) to the reaction mixture. The resulting solution was cooled to room temperature (RT) and stirred for approximately 24 h. The suspension was filtered and the filtrate was stirred at RT for 2 days. The precipitate obtained was filtered and dried in a vacuum oven at about 50 ° C / 20 mbar to give Form I Nilotinib L-tartaric acid hydrochloride cocrystals, as confirmed by XRPD.

Example 6. Preparation of Nilotinib L-Tartaric Acid Hydrochloride Co-Crystals Form I (for reference only) Nilotinib hydrochloride Form T17 (500 mg) and L-tartaric acid (172 mg) were mixed to obtain a homogeneous mixture. 300 mg of mixture was placed in a ball mill (agate, 25 ml) and one drop of abs ethanol was added. The mixture was ground for 2.5 h at 500 rpm with 3 agate beads to provide Form I Nilotinib L-tartaric acid hydrochloride cocrystals, as confirmed by XRPD.

Example 7. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) A suspension of Nilotinib hydrochloride Form T17 (56.6 mg) and L-tartaric acid (15.0 mg) in ethanol abs. (1 ml) was stirred for 36 hours at 35 ° C. The resulting suspension was filtered and the obtained solid was dried in vacuo at RT to provide the Nilotinib hydrochloride cocrystal L-tartaric acid Form I, as confirmed by XRPD.

Example 8. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) A suspension of Nilotinib hydrochloride (1.0 g) and L-tartaric acid (0.5 g) in abs. Ethanol. (40 ml) was heated under reflux. The obtained solution was cooled to room temperature (RT) and stirred for about 2 h. The precipitate obtained was filtered to provide Nilotinib L-tartaric acid hydrochloride cocrystals Form I, as confirmed by XRPD.

Example 9. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) A suspension of Nilotinib hydrochloride (300 mg) and L-tartaric acid (160 mg) was dissolved in methanol / water 9: 1 (10 ml) at 70 ° C. The reaction mixture was stirred for 15 min at 70 ° C and then cooled to RT. The crystals obtained were filtered, washed with methanol / water 9: 1 and dried in a vacuum oven for 2 h at 50 ° C / 10 mbar to provide Form I Nilotinib L-tartaric acid hydrochloride cocrystals, as was confirmed by XRPD. Example 10. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form II (for reference only) A suspension of Nilotinib hydrochloride form T17 (56.6 mg) and L-tartaric acid (15.0 mg) in tetrahydrofuran (1 ml) for 36 hours at 35 ° C. The solid was filtered and dried under vacuum at RT to obtain form II Nilotinib hydrochloride L-tartaric acid cocrystals, as characterized by XRPD (Figure 2).

Example 11. Preparation of Nilotinib Fumarate Form III

Nilotinib base (1.60 kg) and fumaric acid (0.40 kg) were suspended in 1-butanol (60 L). The reaction mixture was heated to about 95 ° C and the obtained solution was filtered. The filtrate was cooled to 76-80 ° C and seeded with Nilotinib fumarate form III (64 g). The reaction mixture was stirred at 76-80 ° C for 1 h, cooled to 48-52 ° C, stirred for 1 h, cooled to 8-12 ° C, and stirred for 4 hours. The solid obtained was filtered, washed twice with 1-butanol (23 L) and dried in a vacuum oven at 65-75 ° C (LOD <1.0%). Nilotinib fumarate Form III was obtained as confirmed by XRPD (1.61 kg).

Example 12. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) Nilotinib hydrochloride (10.0 g) and L-tartaric acid (5.3 g) were dissolved in ethanol, 96% (386 ml) under reflux. The solution was cooled to RT in 1 hour and stirred overnight. The solid was filtered, washed with ethanol, 96% and dried for 2 hours at 50 ° C / 10 mbar. The material obtained corresponds to Form I of Nilotinib L-tartaric acid hydrochloride cocrystals, as confirmed by XRPD.

Example 13. Preparation of Nilotinib hydrochloride L-tartaric acid cocrystals Form I (for reference only) Nilotinib hydrochloride (214.5 g) and L-tartaric acid (114.3 g) were dissolved in methanol / water ( 9: 1 v / v) at 65 ° C in a 6 L glass jacketed reactor. The solution was cooled to 60 ° C in 30 minutes, then to 45 ° C in 40 min, then to 15 ° C in 8 hours, and finally to 5 ° C in 16 hours. The suspension was filtered and washed with methanol / water (9: 1 v / v). The product was dried for 4 hours at 50 ° C / 10 mbar. The material obtained corresponds to Form I of Nilotinib L-tartaric acid hydrochloride cocrystals, as confirmed by XRPD.

Example 14. Preparation of Nilotinib L-tartaric acid hydrochloride cocrystals Form I (for reference only) Nilotinib cocrystals Form I (30 g) (obtained in Example 13 was dried in a vacuum oven for about 8 hours at 100 ° C / 100 mbar The XRPD of the material obtained corresponds to Form I of Nilotinib L-tartaric acid hydrochloride cocrystals.

Claims (15)

1. A crystalline form of Nilotinib fumarate designated Form III, characterized by data selected from one or more of the following: to. an XRPD pattern having peaks at 5.5, 7.0, 11.0, 13.4, and 15.8 degrees two theta ± 0.2 degrees two theta; b. an XRPD pattern substantially as shown in Figure 1; c. and combinations of these data. 2. The crystalline form III of the Nilotinib fumarate according to claim 1, further characterized by data selected from one or more of the following: an XRPD pattern that has peaks at 5.5, 7.0, 11.0, 13.4, and 15.8 degrees two theta ± 0.2 degrees two theta, and also has one, two, three, four, five, six, or seven additional peaks selected from 14.0, 14.9, 16.3, 20.4, 20.5, 20.9, and 25.3 degrees two theta ± 0.2 degrees two theta; an FTIR spectrum having peaks at 3348, 1676, 1560, 1404 and 1296 ± 4 cm -1; an FTIR spectrum substantially as shown in Figure 5; a Raman spectrum having peaks at 1668, 1614, 1407 and 1306 ± 4 cm -1; a Raman spectrum substantially as shown in Figure 6; an endothermic melting DSC peak at about 228 ° C (start); a DSC thermogram substantially as shown in Figure 7; a TGA thermogram substantially as shown in Figure 8; a solid state 123C NMR spectrum having characteristic peaks at 168.9, 159.1, 135.4 and 114.7 ± 0.2 ppm; a solid state 13C NMR spectrum substantially as shown in Figure 4; a solid state 13C NMR spectrum having the following absolute chemical shift differences from a peak at 119.0 ppm ± 1 ppm to 49.9, 40.1, 16.4 and -4.3 ppm ± 0.1 ppm; a solid state 13C NMR spectrum having a chemical shift difference from a peak at 119.0 ppm ± 1 ppm to 40.1 ppm ± 0.1 ppm; and combinations of these data. 3. The crystalline form III of Nilotinib fumarate according to claim 2, characterized by an XRPD pattern having peaks at 5.5, 7.0, 11.0, 13.4 and 15.8 degrees two theta ± 0, 2 degrees two theta and also characterized by also having one, two, three, four, five, six or seven additional peaks selected from 14.0, 14.9, 16.3, 20.4, 20.5, 20.9 and 25.3 degrees two theta ± 0.2 degrees two theta. 4. The crystalline form III of Nilotinib fumarate according to any one of claims 1 to 3, wherein the crystalline form is in anhydrous form. 5. A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 4. 6. Use of the crystalline form according to any one of claims 1 to 4 in the production of pharmaceutical compositions and / or formulations. 7. A pharmaceutical formulation comprising a crystalline form according to any one of claims 1 to 4 or the pharmaceutical composition of claim 5, and at least one pharmaceutically acceptable excipient. A process for preparing the pharmaceutical formulation according to claim 7, which comprises combining a crystalline form according to any one of claims 1 to 4 or the pharmaceutical composition of claim 5, with at least one pharmaceutically acceptable excipient. The crystalline form according to any one of claims 1 to 4, the pharmaceutical composition according to claim 5 or the pharmaceutical formulation according to claim 7, for use as a medicine. 10. The crystalline form, according to any one of claims 1 to 4, the pharmaceutical composition according to claim 5, or the pharmaceutical formulation according to claim 7, for use in the treatment of cancer, preferably CML . 11. Use of the crystalline form III of Nilotinib fumarate according to any one of claims 1 to 4 in the preparation of another solid state form of Nilotinib fumarate. 12. Use of the crystalline form III of Nilotinib fumarate according to any one of claims 1 to 4 in the preparation of the Nilotinib base, or a solid state form thereof, or a Nilotinib salt, or a shape in solid state of it. The use of claim 12, wherein the Nilotinib salt, or its solid state form, is Nilotinib hydrochloride. 14. A process for preparing the base of Nilotinib, or a solid state form thereof, or a Nilotinib salt, or a solid state form thereof, which comprises preparing the crystalline Form III of Nilotinib fumarate according to with any one of claims 1 to 4, and converting it into a Nilotinib base, or a solid state form thereof, or a Nilotinib salt, or a solid state form thereof. 15. The process of claim 14, wherein the Nilotinib salt, or its solid state form, is Nilotinib hydrochloride.